title: Pyridinium derivatives of histamine are potent activators of cytosolic carbonic anhydrase isoforms I, II and VII.
abstract: A series of positively-charged derivatives has been prepared by reaction of histamine with substituted pyrylium salts. These pyridinium histamine derivatives were investigated as activators of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1) and more precisely the human isoforms hCA I, II and VII. Activities from the subnanomolar to the micromolar range were detected for these compounds as activators of the three isoforms, confirming the validity of current and previous designs. The substitution pattern at the pyridinium ring was the main factor influencing activity, the three isoforms showing different structural requirements for good activity, related with the number of pyridinium substituting groups and their nature, among various alkyl, phenyl and para-substituted styryl moieties. We were successful in identifying nanomolar potent and selective activators for each isozyme and also activators with a relatively good activity against all isozymes tested--valuable lead compounds for physiology and pathology studies involving these isozymes.
authors.affiliation: Temple University School of Pharmacy, Department of Pharmaceutical Sciences, 3307 North Broad Street, Philadelphia, PA 19140, USA.
authors.forename: Khyati
authors.initials: K
authors.lastname: Dave
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Marc A
authors.initials: MA
authors.lastname: Ilies
mesh_terms: D000818:Animals; D024401:Carbonic Anhydrase I / Q000378:metabolism*; D024402:Carbonic Anhydrase II / Q000378:metabolism*; D030741:Carbonic Anhydrase IV / Q000378:metabolism*; D002417:Cattle; D003600:Cytosol / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D006632:Histamine / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D015394:Molecular Structure; D010621:Phenazopyridine / Q000031:analogs & derivatives*; D013329:Structure-Activity Relationship
chemical_list: D007527:Isoenzymes; D006632:Histamine; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; D030741:Carbonic Anhydrase IV; D010621:Phenazopyridine